JP2009508965A - Pharmaceutical product based on a combined S-nitrosothiol for restoring normal respiratory rhythm - Google Patents

Abstract

  The present invention is directed to a method of treating a lack of normal respiratory control, including the treatment of apnea and hypoventilation associated with sleep, obesity, certain drugs and other medical conditions. In one aspect, the invention provides impaired control of breathing by administering a composition comprising a combination of two or more compounds, wherein at least one of the compounds treats a lack of normal breathing. Opposed to treatment. In one aspect, the compound is an S-nitrosylation agent.

Description

  Normal control of respiration is a complex process that involves the body's judgment and response to chemical stimuli such as carbon dioxide, pH and oxygen levels in the blood, tissues and brain. Respiratory control is also affected by wakefulness (ie, whether the patient is awake or asleep). Within the cerebral medulla there is a respiratory control center that determines the various signals that affect breathing and issue commands to the muscles that perform the breathing task. Key muscle groups are located in the abdomen, diaphragm, pharynx and thorax. Centrally and peripherally located sensors then provide input to the central respiratory control area of the brain that allows response to changes in oxygen demand.

Normal respiratory rhythm is maintained primarily by the body's rapid response to changes in carbon dioxide levels (CO ₂ ). Increased CO ₂ levels signal the body to increase the rate and depth of breathing resulting in higher oxygen levels followed by lower CO ₂ levels. Conversely, a low CO ₂ level will result in an apnea (no breathing) period, as there is no stimulation to breathing. This can happen if a person breathes excessively.

  In addition to the role of the brain, respiration control is the result of feedback from both peripheral and central chemoreceptors—although the exact contribution of each is unknown.

There are a wide variety of diseases that have a loss of normal respiratory rhythm as a primary or secondary feature of the disease. Primary loss of respiratory rhythm control is apnea (central, mixed and obstructive, with respiration stopping for 10-60 seconds) and congenital central hypoventilation syndrome. Secondary loss of respiratory rhythm can be due to chronic cardiopulmonary disease (eg, heart failure, chronic bronchitis, emphysema and impending respiratory failure), overweight (eg, obesity-hypoventilation syndrome), certain drugs (eg, anesthesia) Drugs, sedatives, anxiolytics, hypnotics, alcohol, narcotic analgesics) and / or factors affecting the nervous system (eg, stroke, tumor, trauma, radiation damage, ALS). In chronic obstructive pulmonary disease where the body is chronically exposed to low levels of oxygen, the body is brought to low pH by renal-mediated retention of bicarbonate, which has the effect of partially neutralizing CO ₂ / pH respiratory stimulation. To adapt. Thus, patients must rely on hyposensitive oxygen-based systems.

In particular, loss of normal respiratory rhythm during sleep is a common symptom. Sleep apnea is characterized by frequent apnea or partial breath periods. Key factors contributing to these apneas include a decrease in CO ₂ receptor sensitivity, a decrease in hypoxic ventilation response sensitivity (eg, a decreased response to hypoxic levels) and a loss of “wakefulness”. Normal breathing rhythm is disturbed, leading to hypoxia (and associated oxidative stress) and ultimately severe cardiovascular consequences (hypertension, stroke, heart attack). Snoring has several characteristics combined with sleep apnea. The upper airway muscles lose their tone, leading to inefficient airflow that will result in hypoxia as well as the sounds associated with snoring.

  The critical treatment for many respiratory control disorders is mechanical ventilation or a positive airway pressure device (eg, continuous positive airway pressure device (CPAP device), 2-level positive airway pressure device (BiPAP device) ) Several pharmacological agents have been proposed as interventions to control respiration in sleep-related breathing disorders. De Backer provided a review and described Progestin, Almitrine, and Acetazolamide (1). Hudgel and Thanakicharu also provide a review of pharmacological treatment of sleep-disordered breathing and, in addition to other agents, medroxyprogesterone, thyroid replacement, acetazolamide, Theophylline, tricyclic antidepressants, serotonin reabsorption inhibitors and clonidine have been described (2). In 2005, Qureshi and Lee-Chiong provided a review of various medical options for treating obstructive sleep apnea, including a wide variety of pharmacological treatments. Several agents included agents that affect serotonin, such as benzodiazepines, narcotics, acetazolamide, antidepressants, and agonists, reabsorption inhibitors or antagonists (Non-Patent Document 3). .

  In particular, DeBacker pointed out that a low dose of the carbonic anhydrase inhibitor acetazolamide appears to exert beneficial effects not related to its traditional action of lowering pH as a respiratory stimulation mechanism. . In a small uncontrolled clinical study in patients with central apnea, low-dose acetazolamide reduces apnea episodes from 25.5 before treatment to 6.8 one month after treatment (73%) Was found. A relatively low decline (about 25%) was seen in patients with significantly obstructive sleep apnea.

  More recently, Carley and Radulovacki have described the use of serotonin agonist / antagonist combinations to increase the motor tone of the throat that disintegrates in obstructive sleep apnea (4). This concept is currently being developed commercially by a community consisting of Organon and Cypress Bioscience and another group, BTG, plc (see, for example, US Pat.

  Gaston and Gozal proposed a fundamentally different approach by demonstrating that the S-nitrosothiol signaling pathway can be used to control respiration by increasing minute ventilation (US Pat. Which is fully incorporated herein by reference). They first demonstrated that a centrally mediated hypoxic ventilation response system is under the control of certain S-nitrosothiol compounds. Gaston and Gozal illustrate a group of compounds that, among other reactions, can induce the body's typical response to hypoxic levels that cause an increase in the rate and depth of respiration.

  The ability of mammals to breathe and modify respiration according to the amount of oxygen available and the body's demand is essential for survival. There are a variety of symptoms characterized by loss of respiratory rhythm due to either primary or secondary causes. Individuals affected for some of the most common symptoms in the United States are: sleep apnea: 1.5-20 million; obesity-hypoventilation syndrome: 0.5-10 million; chronic heart Disease: 5 million; Chronic obstructive pulmonary disease (COPD) / chronic bronchitis: 10 million; Drug-induced underventilation: 2-5 million; and mechanical ventilation withdrawal: 0.5 million including.

  Respiratory control is a complex process. It requires a respiratory drive and also the diameter of the tube where the air flow occurs. For example, imagine an animal breathing through a straw. If the straw is dry and the walls are stiff, air will flow smoothly in both inspiration (negative pressure) and expiration (positive pressure). However, when the straw gets wet, the walls collapse during inhalation and the animal cannot inhale any air. This “wet straw” example partially represents what happens in a patient suffering from sleep apnea. When a patient with sleep apnea goes to sleep, respiratory motives decrease, muscle tone in the airway decreases, and the airway collapses during inspiration, causing an obstruction to normal breathing. The current treatment for sleep apnea is primarily the use of positive airway pressure (PAP) devices. Compliance with these devices is usually very poor. Pharmaceutical products that can be used alone or as an adjunct to positive airway pressure devices to reduce the pressure required to maintain airway capacity are not complied with by these PAP devices. Either an improvement or providing an alternative to treatment would be an important advance.

Thus, a combined pharmaceutical product that can restore all or part of the body's normal respiratory control system in response to changes in CO ₂ and / or oxygen is associated with the occurrence and severity of impaired respiratory control. Would be beneficial in reducing There is currently an unmet need for such products that can be administered to patients with minimal side effects. The present invention addresses and addresses this need.
US Patent Application Publication No. 20060039866 US Patent Application Publication No. 20060039867 US Patent Application Publication No. 20060122127 International Patent Application Publication No. WO03 / 015605 DeBacker WA, 1995 Eur. Respir. J. et al. 8: 1372-1383 Hudgel DW and Thanakitcharu S. 1998 Am J Respir Crit Care Med 158: 691-699. Qureshi A and Lee-Chiong, JR, TL Sem. Resp Crit Care Med 2005; 26: 96-108 Carley and Radulovacki, 1999, Am. J. et al. Respir. Crit. Care Med. 160: 1824-1829

  The present invention provides a first composition comprising an S-nitrosothiol first compound and a second composition comprising a second compound that is not an S-nitrosothiol compound, A therapeutic composition for stabilizing respiratory rhythm comprising a composition wherein the compound has an activity of stabilizing respiratory rhythm.

  In certain embodiments, the second compound is selected from the group consisting of carbonic anhydrase inhibitors, serotonin agonists, serotonin antagonists, NADPH oxidase inhibitors, leukotriene antagonists, COX-2 inhibitors and theophylline. In one embodiment, the carbonic anhydrase inhibitor is selected from the group consisting of acetazolamide and topiramate. In another embodiment, the second compound is a tetracyclic antidepressant selected from the group consisting of mirtazipine and septitline.

  In other embodiments, the serotonin agonist is selected from the group consisting of mirtazapen, buspirone, and a serotonin reabsorption inhibitor. In certain embodiments, the serotonin antagonist is ondansetron.

  In another embodiment, the present invention provides NADPH selected from the group consisting of apocynin, 4-hydroxy-3'-methoxyacetophenone, N-vanillylnonanamide and staurosporine. Contains an oxidase inhibitor.

  The present invention provides a first composition comprising an S-nitrosothiol first compound and a second composition comprising a second compound that is not an S-nitrosothiol compound, A method of stabilizing a respiratory rhythm of a mammal comprising administering to the mammal a therapeutic composition comprising a composition wherein the compound has an activity that stabilizes the respiratory rhythm.

  The present invention includes a therapeutic composition further comprising a third compound, wherein the third compound is an S-nitrosothiol compound. The present invention also includes a therapeutic composition further comprising a third compound, wherein the third compound is not an S-nitrosothiol compound.

  The present invention includes a pharmaceutical composition comprising a composition as described herein and a pharmaceutically acceptable carrier.

  The present invention includes a method of stabilizing a respiratory rhythm of a mammal comprising administering to the mammal a therapeutic composition as described herein.

  The present invention also provides a method for stabilizing the respiratory rhythm of a mammal, the method comprising administering the therapeutic composition of claim 1 to the mammal, said method comprising providing the mammal with a ventilatory assist device. A method further comprising treating. In some embodiments, the ventilation assist device is selected from the group consisting of a CPAP device and a BiPAP device.

  In the method of the present invention, the route of administration is selected from the group consisting of parenteral, oral and buccal. In certain embodiments, the parenteral route of administration is selected from the group consisting of transdermal, intravenous, intramuscular and intradermal. In other embodiments, the composition is administered by at least two routes of administration.

The present invention provides a first composition comprising an S-nitrosothiol first compound; and a second composition comprising a second compound that is not an S-nitrosothiol compound, A therapeutic composition comprising: a compound having an activity of increasing minute ventilation (V _E ) at the level of a brainstem respiratory control center in the nucleus bundle nucleus (nucleus tractus solitarius); A method of increasing fine ventilation (V _E ) at the level of the brainstem respiratory control center in the individual's arc bundle nucleus, including steps.

  For the purpose of illustrating the invention, certain embodiments of the invention are depicted in the drawings. However, the invention is not limited to the exact arrangement and means of the embodiments depicted in the drawings.

  FIG. 1 illustrates the complex and interrelated nature of mammalian respiratory control.

  FIG. 2 including FIG. 2A-2C specifically illustrates factors that affect respiratory control. FIG. 2A specifically illustrates the factors that affect normal respiratory control. Normally, respiratory drivers can act across a range of conditions, and carbon dioxide and oxygen levels are the main drivers and work in an interrelated manner. FIG. 2B illustrates factors that affect impaired respiratory control. A wide range of factors work individually or in combination to reduce respiratory motives resulting in respiratory arrest or inadequate breathing. The ultimate ending is hypoxia with cardiovascular, neurological and / or metabolic consequences. FIG. 2C illustrates the factors considered for effective drug treatment of impaired respiratory control. Drugs are useful to help restore respiratory motives through defined routes or by improving air flow in the upper respiratory tract. The ultimate ending is to reduce impaired breathing (eg apnea, hypopnea, hypoventilation), hypoxia and related consequences in one embodiment of the invention.

  The present invention provides a combination, or “multi-drug, for treating sleep apnea by combining hypoxic ventilatory response control by administration of S-nitrosothiol with other drugs that provide admirable activity. (Multi-drug) ", the approach.

  The present invention provides that a composition comprising a combination of two or more compounds acts on two or more physiological pathways where one of the pathways is affected by S-nitrosothiol treatment for recovery of respiratory rhythm. This provides that it may provide enhanced effectiveness in the treatment of respiratory control disorders. In another aspect of the invention, a composition comprising a combination of two or more compounds provides enhanced efficacy in treating respiratory control disorders by acting on the same physiological pathway. Also good.

  Poor or inefficient respiratory drivers result in hypoventilation, which in turn leads to hypoxia. The main early clinical manifestation of hypoxia is congested state or excessive daytime sleepiness. Therefore, drugs that cause reduced respiratory motives and the resulting hypoxia may negatively impact life essence, threatening life-threatening respiratory depression and / or excessive daytime sleepiness Therefore, their usefulness is sometimes limited. Another consequence of hypoxia from respiratory insufficiency is oxidative stress associated with long-term cardiovascular and / or metabolic consequences. Combined products combining an agent that helps reduce oxidative stress, along with a compound that restores respiratory rhythm, can provide an important dual action mode that reduces the short and long-term consequences of hypoxia.

  As described herein, combination compositions comprising S-nitrosothiol compounds to counteract the respiratory depressant effects of drugs that reduce respiratory motives help maintain normal oxygen levels in blood and tissues Can provide benefits to the patient. By way of non-limiting example, anesthetic analgesics (eg, morphine, fentanyl, oxycodone, buprenorphine) are administered to cancer patients to relieve pain. This dose is often limited by the fear of respiratory depression. In addition, partial respiratory depression with these drugs causes hypoxia and excessive daytime sleepiness derived from it, which can debilitate and severely reduce the quality of life. Common anesthetics can exert a similar inhibitory effect on breathing and delay the patient's transition from the operating room to the surgical recovery area. Therefore, a combination composition comprising an S-nitrosothiol compound is useful to counteract the protracted effects of anesthetics and restore sufficient respiratory motives to make the patient breathable on their own.

  As another non-limiting example, overweight can reduce respiratory motives, which leads to hypoventilation and hypoxia. This condition is called obesity-hypoventilation syndrome. Excess weight is also a risk factor in sleep-related breathing disorders. Thus, a combination composition comprising an S-nitrosothiol compound is useful for counteracting the obesity respiratory depression effect.

  The combination composition of the present invention also increases upper airway muscle tone, improves ventilation / perfusion adaptation, and, inter alia, reduces erythropoietin production as described herein. Useful for increasing.

<Detailed Description of the Invention>
Definitions As used herein, each of the following terms has the meaning associated with it in this section.

  The articles “a” and “an” are used herein to refer to one or more (at least one) of the grammatical purposes of the article. By way of example, “an element” means one or more elements.

  The term “about” can be understood by those skilled in the art and can vary to some extent in the context in which it is used.

  As used herein, the term “apnea” means the absence of normal breathing resulting in intermittent cessation of breathing.

  “Antisense” specifically refers to the nucleic acid sequence of the non-coding strand of a double-stranded DNA molecule encoding a polypeptide, or a sequence that is substantially homologous to the non-coding strand. As defined herein, an antisense sequence is complementary to the sequence of a double-stranded DNA molecule that encodes a polypeptide. It is not necessary that the antisense sequence is complementary only to the coding portion of the coding strand of the DNA molecule. The antisense sequence may be complementary to a particular regulatory sequence on the coding sequence of the DNA molecule encoding the polypeptide, which regulatory sequence controls the expression of the coding sequence.

  “Cheyne-Stokes breathing” refers to a specific breathing pattern characterized by an intensifying pattern of breathing that results in apnea and / or hypopnea. A prominent feature of this symptom is that breathing is out of phase with the blood oxygen level.

  As used herein, “endogenous” refers to all materials produced from within or within an organism, cell, tissue or system.

  As used herein, the term “exogenous” refers to any material that is introduced from or produced outside a living organism, cell, tissue or system.

  As used herein, the term “expression” is defined as the transcription and / or translation of a particular nucleotide sequence operated by its promoter.

  As used herein, the term “expression vector” refers to a vector containing a nucleic acid sequence encoding at least a portion of a gene product capable of being transcribed. In some cases, the RNA molecule is then translated into a protein, polypeptide or peptide. In other cases, these sequences are not translated, for example, in the production of antisense molecules, siRNA, ribozymes and the like. An expression vector may contain various regulatory sequences, which refer to nucleic acid sequences that are essential for transcription and possibly translation of the operably linked coding sequences in a particular host organism. In addition to regulatory sequences that govern transcription and translation, vectors and expression vectors may contain nucleic acid sequences that serve other functions as well.

  “Hypnea” is in many ways similar to apnea; however, breathing does not stop completely, but is partially stopped (ie, less than 100% of normal breathing but normal breathing). Of 0% or more). Hypopnea is also referred to herein as “partial apnea” and can be subdivided into obstructive, central or mixed types.

  An “isolated nucleic acid” is a nucleic acid segment or fragment that is separated from the sequences that naturally flank it, ie, sequences that normally flank the fragment, ie, fragments in the genome in which it naturally occurs. Refers to a DNA fragment removed from an adjacent sequence. The term also applies to nucleic acids that have been substantially purified from other components that naturally accompany the nucleic acid, ie, RNA or DNA or proteins that naturally accompany it in the cell. Thus, this term is incorporated in, for example, a vector, in an autonomously replicating plasmid or virus, or in a prokaryotic or eukaryotic genomic DNA or otherwise independent of other sequences. Recombinant DNA present as a molecule (ie, as a cDNA or genomic or cDNA fragment produced by PCR or restriction enzyme digestion) is included. It also includes recombinant DNA that is part of a hybrid gene encoding additional polypeptide sequences.

  As used herein, the term “modulate” is meant to refer to any change in a biological state, ie, increase, decrease, etc.

  As used herein, the term “promoter / regulatory sequence” means a nucleic acid sequence required for expression of a gene product operably linked to a promoter / regulatory sequence. In some examples, this sequence may be a core promoter sequence, and in other examples this sequence may also include enhancer sequences and other regulatory elements required for expression of the gene product. The promoter / regulatory sequence may, for example, be one that expresses the gene product in a tissue specific manner.

  As used herein, a “pharmaceutically effective amount” is an amount of a therapeutic composition sufficient to provide a beneficial effect to the mammal to which the composition is administered. .

  As the term is used herein, the “S-nitrosothiol pathway” is a signaling pathway and signal that occurs such that information related to the blood level of oxygen is transmitted to the brain through S-nitrosothiol signaling. Refers to the transmission mechanism.

Explanation
Compositions of the Invention and Uses thereof The present invention includes compositions and methods for treating impaired control of breathing. In one embodiment, the present invention provides methods and compositions for treating sleep apnea.

  During sleep, breathing changes with the time or depth of sleep. Some individuals stop breathing at short intervals. If such apnea episodes become more frequent and last longer, they reduce the body's oxygen levels, which can disrupt sleep. The patient is not fully awake, but is awake from deep sleep and as a result feels tired the next day.

  There are two main types of sleep apnea, and these can occur together. The most common is obstructive sleep apnea, where breathing is usually blocked by a temporary obstruction of the main airway at the back of the throat. This often happens because the throat muscles relax and close the main airways. The breast and diaphragm muscles continue to breathe, but the blockage prevents any airflow. After a short interval lasting a few seconds to a few minutes, the oxygen level drops, so the respiratory effort becomes stronger, which finally opens the blockage and restores air flow. This often occurs with large rough nasal breaths and spasms, so patients are awakened from deep sleep. After several breaths, the oxygen level returns to normal, the patient falls asleep, the main airway muscles relax, and the obstruction occurs again. This cycle is then repeated repeatedly during a sleep phase. Most people with obstructive sleep apnea will snore, suggesting that their main airways are already partially occluded during sleep, but all those who snore have no obstructive sleep apnea. Not necessarily breathing.

  A less common form of sleep apnea is central sleep apnea, so called because central control of breathing is abnormal. This control center is in the brain and its function can be destroyed by various factors. There is no blockage to air flow. Patients with sleep apnea stop breathing because the brain suddenly fails to signal the breast and diaphragm muscles that maintain breathing. These patients do not recover breathing due to rough nasal breathing and body spasms, but simply start and stop breathing at various intervals. Although the mechanism is different from obstructive sleep apnea, sleep is still hampered by the loss of periodic oxygen, and patients suffer from the same daytime symptoms.

  Some patients may also suffer from a combined symptom of two causes of apnea, a disorder called mixed sleep apnea and also referred to as “complex sleep apnea”.

  Sleep apnea should be suspected in individuals who have been pointed out to have excessive daytime sleepiness and other symptoms, especially if they snore and do not sleep well. In general, these patients have had large snoring for many years, are mostly male, and indicate that daytime sleepiness has been a progressive problem for months. Less commonly, they may be troubled by enuresis or wilt. Sleep problems are often exacerbated by alcohol or sedation medications. They are also more easily noticed by the patient's family and friends, especially bed partners.

  It should be understood that the compounds and methods of the present invention are applicable to all other respiratory controls associated with the S-nitrosothiol signaling pathway. That is, the present invention relates to two or more physiological pathways in which a composition comprising a combination of two or more compounds is affected by S-nitrosothiol treatment, one of the pathways for recovery of respiratory rhythm. It is possible to provide an enhanced effectiveness in the treatment of respiratory control disorders by acting on.

  In other aspects of the invention, a composition comprising a combination of two or more compounds can provide enhanced efficacy in the treatment of respiratory control disorders by acting on the same physiological pathway. In one aspect of the invention, the composition is used to treat sleep apnea.

  In accordance with the present invention, the second compound used in conjunction with the S-nitrosothiol compound can be selected for a particular property or activity, as described in detail herein. In one aspect of the invention, the third, fourth or further compound is also a non-S-nitrosothiol compound selected for a particular property or activity, as described in detail herein in detail. It may be. The following are non-limiting examples of such compounds, but should in no way be considered the only such compounds useful in the present invention. When armed with the present disclosure, an expert can identify a second (or third, fourth, fifth, etc.) compound useful in combination with an S-nitrosothiol compound according to the present invention. Can understand.

Table 1. Examples of compounds useful in combination with S-nitrosothiol compounds according to the invention a. Compounds having activity to stabilize respiratory rhythm i. Carbonic anhydrase inhibitor (eg, acetazolamide, topiramate)
ii. Respiratory stimulation (eg caffeine, theophylline)
iii. Narcotic antagonists (eg, naloxone)
iv. Hormones (eg, medroxyprogesterone)
b. Compounds having activity to increase upper airway patency by activity on serotonin, dopamine, norepinephrine or GABA i. Serotonin agonist (eg, 5HT1A agonist buspirone, serotonin reabsorption inhibitor, 5HT3 receptor antagonist, eg ondansetron)
ii. Dopamine and / or norepinephrine agonists (eg, ropinerol, milnacipran)
iii. Tetracyclic antidepressants (eg, mirtazipine, cetiptiline)
c. Compounds having activity of promoting arousal i. Modafinil, r-modafinil, amphetamine)
d. Compounds with activity to reduce epileptic seizures i. Zonisamide
e. Compounds with activity to increase upper airway patency by reducing inflammation i. Antihistamines (eg, cetirizine, azelastine, desloratidine, fexofenadine)
ii. Leukotriene antagonist (eg, montelukast)
iii. 5-lipoxygenase inhibitors (eg, zileuton)
iv. Steroids (eg, fluticasone)
v. COX-2 inhibitor f. Compounds with activity to reduce respiratory motives as a side effect on their main therapeutic effect i. Opioid analgesics (eg, morphine, meperidine, fentanyl, oxycodone, buprenorphine)
ii. Sedative hypnotics (eg, lorazepam, zolpidem, zaleplon)
iii. General anesthetics (eg halothane, enfuran, thiopental)
iv. Ethyl alcohol g. Compounds having activity to improve lung function in diseases such as asthma and / or chronic obstructive pulmonary disease i. Steroids (e.g. budesonide, fluticasone, salmeterol / fluticasone combination)
ii. Bronchodilators (eg salbutamol, salmeterol)
iii. Anticholinergics (eg, tiotropium, ipatropium)
h. Device use to assist breathing through mechanical ventilation or positive airway pressure i. Mechanical ventilator ii. CPAP
iii. BiPAP

  Combination drugs in the pharmaceutical industry are reasonably common and the manufacture and use of such drugs can be understood by those skilled in the art. For example, Adair (R) is a combination of a steroid compound and a bronchodilator compound and is used for the treatment of asthma.

  Combinations comprising two or more compounds according to the invention include, but are not limited to, S-nitrosothiol compounds + acetazolamide (and other carbonic anhydrase inhibitors including topiramate), S Nitrosothiol compound + serotonin agonist agonist (eg 5HT1A agonist buspirone; serotonin reabsorption inhibitor), S-nitrosothiol compound + serotonin antagonist agonist (eg 5HT3 receptor antagonist eg ondansetron), S-nitroso Thiol compound + tetracyclic antidepressant (for example, mirtazipine, cetiptiline), S-nitrosothiol compound + modafinil, S-nitrosothiol compound + r-modafinil, S-nitrosothiol compound + norepinephrine And / or compounds that affect neuronal absorption of dopamine (eg, ropinerol, milnacipran), S-nitrosothiol compounds + zonisamide, S-nitrosothiol compounds + agents that stimulate brain activity and / or are opioid antagonists (Eg, doxapram, naloxone, caffeine), S-nitrosothiol compound + narcotic analgesics that induce respiratory depression (eg, morphine, meperidine, fentanyl, oxycodone, buprenorphine), S-nitrosothiol compound + induce respiratory depression General anesthetics (halothane, enfuran, thiopental), S-nitrosothiol compounds + theophylline, S-nitrosothiol compounds + steroids commonly used to treat asthma or chronic obstructive pulmonary disease and / or Or bronchodilators (eg budesonide, fluticasone, salbutamol, formoterol, salmeterol / fluticasone combination, tiotropium, ipatropium), S-nitrosothiol + antihistamines (eg cetiridine, azelastine, desloratidine, fexofenadine) , S-nitrosothiol compounds + sedative / hypnotics (eg, lorazepam, zolpidem, zaleplon), and S-nitrosothiol compounds in combination with positive airway pressure breathing devices (including CPAP and BiPAP). As described herein, other compounds useful in combination with S-nitrosothiol compounds are described in US Patent Application Publication No. 20060039866, which is fully incorporated herein by reference. ing.

  In one embodiment of the invention, a combination of two or more compounds, wherein at least one compound acts through the S-nitrosothiol pathway, provides an additional or synergistic effect to restore normal respiratory rhythm can do. In another embodiment of the invention, a combination of two or more compounds in which at least one compound acts through the S-nitrosothiol pathway is used for other drugs that may or may not be administered simultaneously. Provides an effect to counteract the respiratory depression effect.

  S-nitrosothiol compounds, or “SNO”, have been described as having various clinical benefits. These include, but are not limited to, an increase in respiratory motives, an increase in muscle tone in the upper respiratory tract, an improved oxygen exchange in the lungs (“adapted ventilation perfusion”), and erythropoietin (EPO), red blood cell production Including increased production of natural hormones. Increased EPO production is particularly useful in patients with respiratory problems (with associated hypoxia) and anemia. Such symptoms result in a “double negative effect” of low oxygen levels and low counts of cells carrying oxygen (eg, premature apnea, renal dialysis patients).

  In one aspect of the invention, the compounds of the invention are useful in the form in which the compound is administered. That is, the chemical structure and formula of a compound administered to a patient is a compound that is active according to the methods of the invention. In other embodiments, the compounds of the invention are active in a form separate from the structure or formula administered to the patient. In this aspect of the invention, the compound must first be altered, added, degraded, metabolized or otherwise modified from the form in which the compound is administered to the patient. As a non-limiting example, N-acetylcysteine (NAC) is one such compound. NAC is administered to a patient as a prodrug, which is metabolized by the body to S-nitrosothiol-N-acetylcysteine (SNOAC). SNOAC, a metabolized compound, subsequently becomes active, for example, in regulating patient breathing. References, eg, International Patent Application Publication No. WO 03/015605, which is fully incorporated herein by reference.

  In other aspects of the invention, the S-nitrosothiol compound is an analog, derivative or modification of a known S-nitrosothiol compound. As some non-limiting examples, S-nitrosothiol compounds encompassed by the present invention include analogs of N-acetylcysteine, derivatives of N-acetylcysteine, modified N-acetylcysteine and N-acetylcysteine. Contains metabolites of acetylcysteine.

  The analogs and derivatives of S-nitrosothiol compounds can be made and used in accordance with the invention described herein by those skilled in the art, given the disclosure described herein. I can understand. One skilled in the art can understand in accordance with the present invention how to identify and modify portions of the S-nitrosothiol compound, and how to make such modifications. Thus, based on the detailed description provided herein, one of ordinary skill in the art will be able to breathe according to the present invention when used in combination with the activity of the compounds of the invention, ie, one or more additional compounds. To identify analogs or derivatives that have the ability to control, one can know how to assay such compounds.

As a non-limiting example, the combination according to the invention comprises acetazolamide combined with N-acetylcysteine. In certain embodiments, a combination according to the invention comprises a low dose of acetazolamide (eg, 250 mg / day or less) combined with N-acetylcysteine. Without wishing to be bound by any theory, the combination of acetazolamide and N-acetylcysteine can act complementary or synergistically in a manner that restores normal respiratory rhythm. Acetazolamide can act to restore the body's sensitivity to CO _2, and the N- acetylcysteine, may act to restore sensitivity of the respiratory center to low oxygen levels.

  Acetazolamide has been used for many years as a weak diuretic (ie, to increase urinary excretion or to help treat altitude sickness). Acetazolamide is also thought to act through the respiratory motive pathway based on carbon dioxide. Although it has been proposed to work by lowering the pH of the blood, this may not be the only way it affects respiratory motives. The decrease in respiratory motives may be caused by a poor function of the carbon dioxide component, the oxygen component, or both components together. These components are in fact correlated and causing an effect on one component will affect other components and the overall respiratory motive.

Thus, in one embodiment of the invention, in cases such as sleep apnea where both CO ₂ and O ₂ motives are reduced, the combination composition provides a clinical benefit and / or treatment for the patient. Used for. That is, in one embodiment, the present invention provides a method of treating sleep apnea.

  Traditional thinking has previously been that the dose of acetazolamide required for treatment is very toxic for long-term use in the majority of patients. However, a relatively low dose of acetazolamide will be sufficient to produce the desired effect on respiratory motives, particularly in combination with one or more other ingredients according to the present invention. Other compounds that are more effective at lower doses include, but are not limited to, theophylline due to the spread of side effects when used at higher doses.

  The combination composition according to the invention is useful for treating all symptoms characterized by a lack of normal respiratory control. By way of non-limiting example, such symptoms include sleep apnea (central, mixed and obstructive including but not limited to heart failure, kidney disease and stroke comorbidities), sleep disorder Includes breathing (especially with snoring and awakening), chronic bronchitis, COPD, asthma, allergies and neurological disorders (eg, stroke, amyotrophic lateral sclerosis (ALS)). Other conditions that can be treated by the methods and compositions of the present invention include, but are not limited to, snoring, obesity-hypoventilation syndrome, premature apnea, drugs (eg, anesthetic analgesics, sedatives, alcohol, Respiratory depression with sleep pills, anesthetics, central congenital hypoventilation syndrome, stroke, trauma, hypoventilation with surgery and / or irradiation, and adaptation to high altitude.

  The combination composition according to the present invention is also useful to help treat all symptoms that can be treated using a positive airway pressure (PAP) device as described elsewhere herein.

  By way of non-limiting example, the present invention may also be used to treat and / or alleviate symptoms of high altitude adaptation or to facilitate high altitude adaptation. Genetic diversity plays a role in how humans respond to hypoxia levels. Some respond quickly by increasing the speed and depth of breathing, while others are relatively slow. There are some cases where the ability to adapt quickly is important. For example, soldiers that quickly enter combat at high altitudes (eg, 12,000 feet in Afghanistan) need to perform military operations with maximum performance. A slow response to hypoxia will result in excessive fatigue and poor work performance. For soldiers, this will be life threatening. At the extreme altitude listed, the case is fairly clear. It may also be applied at relatively low altitudes such as travel from New York to Denver (5,000 feet) or jet lag from long aircraft flights (6000 feet of in-flight pressure).

  Serotonin agonists or reabsorption inhibitor compounds (eg, mirtazapine) have been demonstrated in animals to help collapse upper airway tension and prevent collapse. In one aspect of the invention, an SNO / serotonin agonist combination composition is used, where SNO is used to improve respiratory motives, and serotonin agonists improve upper airway tone and Helping the flow of blood and preventing blockage.

  In other embodiments, the invention includes a combination of an agent and SNO intended to reduce oxidative stress. When the body stops breathing and oxygen levels fall, there are a series of reactions that result in oxidative stress that is believed to be a direct cause of cardiovascular complications associated with sleep apnea and other symptoms. Cardiovascular complications are a major cause of death.

  In one aspect of the invention, the combination composition comprises N-acetylcysteine, which is used to reduce oxidative stress through metabolic pathways that are not related to SNO production. That is, the invention is also limited to N-acetylcysteine or other SNO-containing compounds, other drugs, second SNOs that act to increase the respiratory motives of the second compound, or non-SNO compounds, such as Including, but not limited to, acetazolamide, methods and combination compositions that reduce oxidative stress in combination. Other combinations useful in the methods and compositions of the present invention can be understood by one of ordinary skill in the art having the disclosure described in this disclosure.

  In other aspects, the invention includes a combination composition comprising an SNO compound and a compound that treats and / or prevents oxidative stress in a mammal. In one embodiment, the invention includes a method of treating a patient lacking normal breathing by administering a compound of the invention.

  Frequent hypoxia / reoxygenation events that replicate the oxygenation pattern in sleep apnea include neurons that are NADPH oxidase in one embodiment and arousal-active neurons in another embodiment Induces proflammatory gene expression in selected brain regions. In one embodiment, the lack of functional NADPH oxidase and the pharmacological inhibition of NADPH oxidase confer resistance to redox and pre-inflammatory changes of neurobehavioral from intermittent hypoxia. Was determined, thereby highlighting a potential target for preventing oxidative morbidity in people with obstructive sleep apnea (OSA).

  US Patent Application Publication No. 20060154856, which is fully incorporated herein by reference, identifies NADPH oxidase as an important source of intermittent hypoxia-induced injury in the brain. In other embodiments, activation of NADPH oxidase in a person with OSA contributes to the cardiovascular morbidity associated with the disease. Thus, the NADPH oxidase pathway is a valuable drug therapy target associated with prevalent disorders, sleep apnea neurobehavioral and cardiovascular pathological conditions. According to one aspect of the invention, the invention comprises administering to a subject a therapeutically effective amount of a composition comprising an NADPH oxidase inhibitor and at least one other compound. Methods of treating cardiovascular morbidity, neurobehavioral morbidity, or a combination thereof resulting from sleep apnea, hypopnea syndrome in a subject are provided. In one embodiment, the at least one other compound is an inhibitor of the S-nitrosothiol signaling pathway. NADPH oxidase inhibitors include, but are not limited to, apocynin, or 4-hydroxy-3'-methoxyacetophenone, N-vanillyl nonanamide and staurosporine.

  In other embodiments, the invention includes a combination of SNO and an agent intended to reduce inflammation. Examples include leukotriene receptor antagonists (or 5-lipoxygenase inhibitors), antihistamines or anti-inflammatory agents (eg, COX-2 inhibitors or steroids). In one aspect, the invention includes a method of using a combination composition to treat a patient lacking normal breathing.

  Patients with sleep disordered breathing have turbulent airflow that causes inflammation and reduces their ability to acquire enough air. As discussed elsewhere herein, SNO compounds can increase respiratory motives and increase the diameter of the upper airway passage. Thus, according to the present invention, combination compositions comprising SNO plus anti-inflammatory compounds are useful for providing supplemental therapeutic benefits (Goldbart et al, Am. J. Respir. Crit. Care. Med. 2005; 172: 364-370).

  As a non-limiting example, leukotriene antagonist therapy using the compositions and methods of the present invention reduces inflammation resulting from turbulent airflow and regulates the breathing of patients suffering from a lack of normal breathing be able to. This is why turbulent air flow causes inflammation that further restricts air flow because inflammation reduces the size of the airway passage. In accordance with the present invention, combination composition products comprising anti-inflammatory agents are useful to provide additional benefits for both adult and child patients with various forms of sleep disordered breathing.

  In one aspect of the invention, an SNO prodrug (eg, N-acetylcysteine) or SNO in combination with a leukotriene antagonist (or 5-lipoxygenase oxidase inhibitor) simultaneously induces inflammation associated with such respiratory disorders. Useful for treating impaired control of breathing while minimizing.

  In such aspects of the invention, the invention includes a combination composition comprising three or more compounds for the treatment of a disease or disorder associated with a lack of normal respiratory control. The invention also includes a method of treating a mammal, wherein the method uses a combination composition comprising three or more compounds for the treatment of a disease or disorder associated with a lack of normal respiratory control. The composition according to the invention may comprise one or more SNO compounds. In other embodiments, the composition according to the invention may comprise more than two non-SNO compounds. Compounds useful in the combination compositions of the invention are described in detail elsewhere herein.

  In another aspect of the invention, a method of treating a patient lacking normal breathing comprises administering a compound of the invention as described herein and further treating a lack of normal breathing. Treating a patient using the device. As described in detail elsewhere herein, such devices include, but are not limited to, CPAP and BiPAP devices.

Pharmaceutical Compositions The present invention also encompasses the use of suitable protein or peptide and / or isolated nucleic acid pharmaceutical compositions to carry out the methods of the invention. Compositions and combinations of the compounds described herein may be used alone or in addition to produce additional, complementary or synergistic effects in the treatment of impaired breathing and the treatment of respiratory disorders associated with sleep. It can be used in combination with a compound.

  In certain embodiments, pharmaceutical compositions useful for practicing the invention may be administered to deliver a dose of 1 ng / kg / day to 100 mg / kg / day. In other embodiments, pharmaceutical compositions useful for practicing the invention may be administered to deliver a dose of 1 ng / kg / day to 500 mg / kg / day.

  Useful pharmaceutically acceptable carriers include, but are not limited to, salt solutions such as glycerol, water, saline, ethanol and other pharmaceutically acceptable phosphate and organic acid salts. Including. Examples of these and other pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey).

  The pharmaceutical compositions may be manufactured, packaged or sold in the form of a sterile injectable aqueous or oleaginous suspension or solution. This suspension or solution may be formulated according to known techniques and may contain, in addition to the active ingredient, further ingredients described herein, such as dispersing, wetting or suspending agents. Good. Such sterile injectable formulations may be prepared, for example, using non-toxic parenterally acceptable diluents or solvents, such as water or 1,3-butanediol. Other diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides.

  The pharmaceutical compositions useful in the methods of the invention are suitable for oral, intraanal, intravaginal, parenteral, topical, pulmonary, intranasal, buccal, intraocular administration, or other routes of administration. It may be administered, manufactured, packaged, and / or sold in a formulation. Other contemplated formulations include ejected nanoparticles, liposome preparations, resealed erythrocytes containing active ingredients, and immunological formulations.

  The compositions of the present invention can be administered via a variety of administration routes including, but not limited to, oral, intraanal, intravaginal, parenteral, topical, pulmonary, intranasal, buccal or intraocular routes of administration. It may be administered. The route of administration will be readily apparent to those skilled in the art and will depend on a number of factors, including the type and severity of the disease being treated, the type and age of the domestic or human patient being treated, etc. I will.

  The pharmaceutical compositions useful in the methods of the present invention may be administered systemically in oral solid formulations, eye drops, suppositories, aerosols, topical or other similar formulations. In addition to compounds such as heparin sulfate or biological equivalents thereof, such pharmaceutical compositions contain known pharmaceutically acceptable carriers and other ingredients to enhance and facilitate drug administration. You may contain. Other possible formulations, such as nanoparticles, liposomes, resealed erythrocytes, and immunological systems may also be used to administer compounds according to the methods of the invention.

  Compounds identified using any of the methods described herein, and combinations of such compounds, are formulated for treatment of impaired respiratory control and administered to a mammal. May be.

  Such pharmaceutical compositions may consist of the single active ingredient in a form suitable for administration to a subject, or the pharmaceutical composition comprises at least one active ingredient and one active ingredient. The above pharmaceutically acceptable carriers, one or more additional ingredients, or some combination thereof may be included. The active ingredient may be present in a pharmaceutical composition in the form of a physiologically acceptable ester or salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art.

  The obstacle for topical administration of pharmaceuticals is the stratum corneum of the epidermis. The stratum corneum is a highly resistant layer composed of proteins, cholesterol, sphingolipids, free fatty acids and various other lipids, and includes keratinized and living cells. One factor that limits the penetration rate (flow) of a compound through the stratum corneum is the amount of active substance that can be loaded or applied onto the skin surface. The greater the amount of active substance applied per unit area of skin, the greater the concentration gradient between the skin surface and the lower layer of the skin and then the greater the diffusivity of the active substance through the skin. Thus, a formulation containing a higher concentration of active substance will result in a further penetration of the active substance through the skin, and a formulation having a lower concentration if all else is similar It is believed to bring more of it at a much more consistent rate.

  The pharmaceutical composition formulations described herein can be prepared by all methods known in the art of pharmacology or later developed. In general, such manufacturing methods involve combining the active ingredient with a carrier or one or more other accessory ingredients, and then shaping the product into the desired single or multi-dose units, if necessary or desired. Including packaging.

  Although the description of a pharmaceutical composition provided herein is basically directed to a pharmaceutical composition that is suitable for ethical administration to a human, such a composition is generally any One skilled in the art can appreciate that it is suitable for administration to a variety of animals. In order to make the composition suitable for administration to various animals, modifications of the pharmaceutical composition suitable for administration to humans are well understood, and skilled veterinarians should, if necessary, Such modifications can be designed and implemented by routine experimentation. Subjects contemplated for administration of the pharmaceutical composition of the present invention include, but are not limited to, humans and other primates, commercially relevant mammals such as cows, pigs, horses, sheep, cats and Includes mammals including dogs.

  The pharmaceutical compositions useful in the methods of the present invention are for oral, intraanal, intravaginal, parenteral, topical, pulmonary, nasal, buccal, intraocular, intrapleural administration, or other routes of administration. May be manufactured, packaged, or sold in a suitable formulation. Other contemplated formulations include ejected nanoparticles, liposome preparations, resealed erythrocytes containing active ingredients, and immunological formulations.

  The pharmaceutical compositions of the invention may be manufactured, packaged or sold in bulk as a single unit dose or as multiple single unit doses. As used herein, a “unit dose” is a fractionated amount of a pharmaceutical composition that comprises a predetermined amount of an active ingredient. The amount of active ingredient will generally be the dose of active ingredient that will be administered to a subject, or a convenient fraction of such a dose, such as 1/2 or 1 / of such a dose. Equal to 3.

  The relative amounts of active ingredient, pharmaceutically acceptable carrier and any further ingredients in the pharmaceutical composition of the present invention will depend on the identity, size and symptoms of the subject being treated and the composition It can vary depending on the route of administration. By way of example, the composition may comprise between 0.1% and 100% (w / w) active ingredient.

  Controlled or sustained release formulations of the pharmaceutical compositions of the invention can be made using conventional techniques. Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations such as liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, ointments or pasta. And solutions or suspensions. Formulations that can be administered topically may have an active ingredient concentration as high as the solubility limit of the active ingredient in the solvent, but may include, for example, from about 1% to about 10% (w / w) of the active ingredient . Formulations for topical administration may further include one or more of the additional ingredients described herein.

  Osmosis enhancers may be used. These materials increase the rate of penetration of the drug across the skin. Local enhancers in the art include ethanol, glycerol monolaurate, PGML (polyethylene glycol monolaurate), dimethyl sulfoxide, and the like. Other enhancers include oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkane carboxylic acid, dimethyl sulfoxide, polar lipids or N-methyl-2-pyrrolidone.

  One acceptable medium for topical delivery of some of the compositions of the invention may contain liposomes. Liposome compositions and their use are known in the art (eg, see Contanza, US Pat. No. 6,323,219).

  The origin of the active compound to be formulated will generally depend on the particular form of the compound. Small organic molecules and peptidyl or oligofragments can be synthesized chemically and can be provided in a pure form suitable for pharmaceutical use. Natural extract products can be purified according to techniques known in the art. Recombinant sources of compounds are also available to those skilled in the art.

  In other embodiments, the topically active pharmaceutical composition optionally comprises other ingredients such as adjuvants, antioxidants, chelating agents, surfactants, foaming agents, wetting agents, emulsifiers, It may be combined with thickeners, buffers, preservatives, and the like. In other embodiments, a permeation or penetration enhancer is included in the composition and improves transdermal penetration of the active ingredient into and through the stratum corneum as compared to a composition lacking a permeation enhancer. It is effective to do. Various permeation enhancers are known to those skilled in the art including oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkane carboxylic acid, dimethyl sulfoxide, polar lipids, or N-methyl-2-pyrrolidone. In other embodiments, the composition may further comprise a hydrotropic agent, which functions to increase damage in the stratum corneum structure and increases transport across the stratum corneum. . Various hydrophobic agents such as isopropyl alcohol, propylene glycol or sodium xylene sulfonate are known to those skilled in the art.

  Topically active pharmaceutical compositions should be applied in an effective amount that affects the desired change. As used herein, “effective amount” shall mean an amount sufficient to cover the area of the skin surface where a change is desired. The active compound should be present in an amount of about 0.0001% to about 15% by weight volume of the composition. More preferably, it should be present in an amount from about 0.0005% to about 5% of the composition; most preferably it is present in an amount from about 0.001% to about 1% of the composition. Should. Such compounds may be obtained synthetically or naturally.

  Liquid derivatives and natural extracts made directly from biological sources may be used in the compositions of the present invention at a concentration (w / v) of about 1 to about 99%. The fraction of natural extract and protease inhibitor may have various suitable ranges from about 0.01% to about 20%, more preferably from about 1% to about 10% of the composition. Of course, the active agent mixtures of the present invention may be combined and used together in the same formulation or in successive applications of different formulations.

  The compositions of the present invention may comprise from about 0.005% to 2.0% preservative by total weight of the composition. The preservative is in the environment by exposure to the patient's skin, including contact with the finger, for example, used to apply the composition of the invention, such as air or a therapeutic gel or cream. When exposed to contaminants, it is used to prevent wear as in aqueous gels due to repeated patient use. Examples of preservatives useful in accordance with the present invention include, but are not limited to, those selected from the group consisting of benzyl alcohol, sorbic acid, parabens, imidurea, and combinations thereof. A particularly suitable preservative is a combination of about 0.5% to 2.0% benzyl alcohol and 0.05% to 0.5% sorbic acid.

The composition preferably includes an antioxidant and a chelating agent that prevent degradation of the compound for use in the present invention in an aqueous gel formulation. Suitable antioxidants for some compounds are BHT, BHA, α-tocopherol and ascorbic acid in a preferred range of about 0.01% to 0.3 wt% by total weight of the composition, more preferably 0. BHT in the range of 03% to 0.1 wt%. Preferably, the chelating agent is present in an amount of 0.01% to 0.5 wt% by total weight of the composition. Particularly suitable chelating agents are edetates (e.g., edetate) in the weight range of about 0.01% to 0.20%, more preferably in the range of 0.02% to 0.10 wt%, based on the total weight of the composition. Acid disodium) and citric acid. Chelating agents are useful for chelating metallic iron in compositions that may be detrimental to the shelf life of the formulation. Thus, BHT and disodium edetate are particularly suitable antioxidants and chelators, respectively, for some compounds, but other suitable equivalent antioxidants and chelators known to those skilled in the art. May be substituted.
Controlled release preparations may also be used, and methods of using such preparations are known to those skilled in the art.

  In some cases, the dosage forms used may be, for example, hydropropyl methylcellulose, other polymer matrices, permeable membranes, osmotic systems, multilayer coatings, to provide the desired release profile in the modification of properties. Microparticles, liposomes or microspheres or combinations thereof may be used as a slow or controlled release form of one or more active ingredients therein.

  Suitable controlled release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions of the present invention. Thus, single dosage forms suitable for oral administration adapted for controlled release, such as tablets, capsules, gelcaps and caplets are encompassed by the present invention.

  Most controlled release pharmaceutical products have a common goal of improving drug therapy over that achieved by their uncontrolled counterparts. Ideally, the use of an optimally designed controlled release preparation in a medical procedure is characterized by a minimal amount of drug substance that is used to cure or control symptoms in a minimal amount of time. Advantages of controlled release formulations include extended drug activity, reduced dosing frequency and increased patient compliance. Furthermore, the controlled release formulation can be used to affect the onset time of action or other properties, such as the blood level of the drug, thus affecting the occurrence of side effects.

  Most controlled release formulations first release the amount of drug that quickly produces the desired therapeutic effect, and gradually and continue with another amount of drug to maintain this level of therapeutic effect over time. And is designed to be released. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that can replace the amount of drug being metabolized and excreted from the body.

  Controlled release of the active ingredient can be stimulated by various inducing factors such as pH, temperature, enzymes, water or other physiological conditions or compounds. In the context of the present invention, the term “controlled release component” includes, but is not limited to, a polymer, polymer matrix, gel, permeable membrane, liposome or microsphere or combination thereof that facilitates controlled release of the active ingredient. Is defined herein as a compound comprising

  Liquid suspensions may be prepared using conventional methods to achieve suspension of the active ingredient in an aqueous or oily medium. Aqueous media include, for example, water and isotonic saline. Oily media include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as peanut, olive, sesame or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.

  Liquid suspensions further include, but are not limited to, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavoring agents, coloring agents and sweetening agents. Including one or more additional components may be included. The oily suspension may further contain a thickener. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fat, sodium alginate, polyvinylpyrrolidone, tragacanth gum, arabic gum, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose . Known dispersing or wetting agents include, but are not limited to, naturally occurring phosphatides such as lecithin, alkylene oxide and partial esters derived from fatty acids, long chain fatty alcohols, fatty acids and hexitol, or Condensation products (eg, polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate and polyoxyethylene sorbitan monooleate, respectively) with fatty acid and partial esters derived from anhydrous hexitol. Known emulsifiers include but are not limited to lecithin and arabic gum. Known preservatives include, but are not limited to, methyl, ethyl or n-propyl-para-hydroxybenzoate, ascorbic acid and sorbic acid. Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose and saccharin. Known thickening agents for oily suspensions include beeswax, hard paraffin and cetyl alcohol.

  Liquid solutions of active ingredients in aqueous or oily solvents may be prepared in substantially the same manner as liquid suspensions, the main difference being that the active ingredients are dissolved rather than suspended in the solvent Is a point. It will be understood that the liquid solution of the pharmaceutical composition of the present invention may include each of the ingredients described with respect to the liquid suspension, and that the suspending agent need not necessarily help dissolve the active ingredient in the solvent. The Aqueous solvents include, for example, water and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as peanut, olive, sesame or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.

  Powdered and granular formulations of the pharmaceutical preparations of the present invention may be prepared using known methods. Such formulations may be administered directly to the subject and are aqueous or oily suspensions, for example by forming tablets, filling capsules, or adding aqueous or oily media thereto Or it may be used to make a solution. Each of these formulations may further comprise one or more dispersing or wetting agents, suspending agents and preserving agents. Additional additives such as excipients and sweetening, flavoring or coloring agents may also be included in these formulations.

The pharmaceutical composition of the present invention may also be manufactured, packaged or sold in the form of an oil-in-water emulsion or a water-in-oil emulsion. The oily phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a combination of these. Such compositions are further derived from one or more emulsifiers, such as naturally occurring gums such as arabic gum or tragacanth gum, naturally occurring phosphatides such as soy or lecithin phosphatides, a combination of fatty acid and hexitol anhydride. Or partial esters thereof, such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. These emulsifiers may also contain additional ingredients including, for example, sweetening or flavoring agents.
As used herein, an “oily” liquid is a liquid that contains liquid molecules containing carbon and exhibits a lower polarity than water.

  Formulations of the pharmaceutical compositions of the present invention suitable for oral administration include, but are not limited to tablets, hard or soft capsules, cachets, each containing a predetermined amount of the active ingredient. ), May be manufactured, packaged or sold in the form of individual solid dosage units, including lozenges or lozenges. Other formulations suitable for oral administration include, but are not limited to, powdered or granular formulations, aqueous or oily suspensions, aqueous or oily solutions, pasta agents, gels, toothpastes, Contains mouthwash, coating, mouthwash, or emulsion. The terms mouthwash or mouthwash are used interchangeably herein.

  The pharmaceutical compositions of the invention may be manufactured, packaged or sold in a formulation suitable for oral or buccal administration. Such formulations may include, but are not limited to, gels, solutions, suspensions, pasta agents, toothpastes, mouthwashes or mouth washes, and coating agents. For example, the mouthwash of the present invention comprises approximately 1.4% of the compound of the present invention, chlorhexidine gluconate (0.12%), ethanol (11.2%), sodium saccharin (0.15% ), FD & C BlueNo. 1 (0.001%), peppermint oil (0.5%), glycerin (10.0%), Tween 60 (0.3%) and up to 100% water. In another embodiment, the toothpaste of the present invention comprises a compound of the present invention at about 5.5%, 70% sorbitol (25.0%) in water, sodium saccharin (0.15%), sodium lauryl sulfate (1 .75%), carbopol 934, 6% suspension (15%), spearmint oil (1.0%), 50% sodium hydroxide in water (0.76%), dibasic calcium phosphate dihydrate (45 %) And up to 100% water. The examples of formulations described herein are not necessarily all, and the invention is further described in these formulations and other formulations not described herein but known to those skilled in the art. It is understood to include modifications.

  A tablet comprising the active ingredient may be made, for example, by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets are effective in free-flowing forms such as powdered or granular preparations, optionally mixed with one or more binders, lubricants, additives, surfactants and dispersants The ingredients may be made by compressing in a suitable device. Molded tablets may be made by molding in a suitable device a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to wet the mixture. Pharmaceutically acceptable additives used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, binders and lubricants. Known dispersants include, but are not limited to, potato starch and sodium starch glycolate. Known surfactants include, but are not limited to, sodium lauryl sulfate. Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate and sodium phosphate. Known granulating and disintegrating agents include, but are not limited to, corn starch and alginic acid. Known binders include, but are not limited to, gelatin, arabic gum, pre-gelatinized corn starch, polyvinyl pyrrolidone and hydroxypropyl methylcellulose. Known lubricants include, but are not limited to, magnesium stearate, stearic acid, silica and talc.

  The tablets may be uncoated or they may be coated using known methods to achieve delayed disintegration in the subject's gastrointestinal tract, thereby providing sustained release and absorption of the active ingredient. provide. As an example, glyceryl monostearate or glyceryl distearate may be used to coat tablets. As a further example, tablets may be coated using the methods described in US Pat. Nos. 4,256,108; 4,160,452; and 4,265,874 to control permeability. Release tablets may be formed. Tablets may further contain sweetening agents, flavoring agents, coloring agents, preservatives or some combination of these in order to provide a pharmaceutically beautiful and palatable preparation.

Hard capsules comprising the active ingredient may be made using a physiologically degradable composition such as gelatin. Such hard capsules contain the active ingredient and may contain additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin.
Soft capsules comprising the active ingredient may be made using a physiologically degradable composition such as gelatin. Such soft capsules contain the active ingredient, which may be mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

  Liquid formulations of the pharmaceutical composition of the present invention suitable for oral administration may be in liquid form or in the form of a dry product intended to be reconstituted with water or other suitable medium prior to use. May also be manufactured, packaged and sold.

  The pharmaceutical compositions of the invention may be manufactured, packaged or sold in a formulation suitable for intraanal administration. Such compositions may be present, for example, in the form of suppositories, retention enemas preparations and solutions for rectal or colonic irritation.

  Suppository formulations are non-irritating pharmaceuticals that are solid at normal room temperature (ie, about 20 ° C.) and liquid at the temperature of the subject's anus (ie, about 37 ° C. in healthy humans). It may be made by combining an acceptable additive and an active ingredient. Suitable pharmaceutically acceptable additives include but are not limited to cocoa butter, polyethylene glycol and various glycerides. Suppository formulations may further comprise a variety of additional ingredients including, but not limited to, antioxidants and preservatives.

  Retentive enema preparations or solutions for rectal or colonic irritation may be made by combining the active ingredient with a pharmaceutically acceptable liquid carrier. As is well known in the art, the enema preparation may be administered using a delivery device adapted to the subject's anal anatomy and loaded into the device. Enema preparations may further include various additional ingredients including, but not limited to, antioxidants and preservatives.

  Methods for filling or coating a material with a chemical composition are known in the art and include, but are not limited to, methods for depositing or bonding a chemical composition on a surface, materials synthesis. A method of incorporating a chemical composition in the structure of the material in between (ie, as with a physiologically degradable material) and later, whether dried or not, aqueous or oily in the absorbent material A method of absorbing the solution or suspension.

  As used herein, “parenteral administration” of a pharmaceutical composition is an administration characterized by creating a physical breach in a subject's tissue and the pharmaceutical composition through a breach in the tissue Any route of administration. Thus, parenteral administration includes, but is not limited to, pharmaceutical by injection of the composition, application of the composition through a surgical incision, application of the composition through a non-surgical wound that enters the tissue, etc. Administration of a pharmaceutical composition. In particular, parenteral administration is intended to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrasternal injection, and renal dialysis infusion techniques.

  Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient in combination with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be manufactured, packaged or sold in a form suitable for bolus administration or continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dose forms, such as multi-dose containers containing ampoules or preservatives. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions, pastes, and implantable sustained release or biodegradable formulations in oily or aqueous media. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is reconstituted with a suitable medium (eg, sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition. Provided in a dry (ie, powdered or granular) form.

  The pharmaceutical compositions may be manufactured, packaged, or sold in the form of a sterile injectable aqueous or oleaginous suspension or solution. This suspension or solution may be formulated according to known techniques and may contain, in addition to the active ingredient, further ingredients described herein, such as dispersing, wetting or suspending agents. . Such sterile injectable formulations may be prepared using, for example, a non-toxic parenterally acceptable diluent or solvent, such as water or 1,3-butanediol. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides. Other parenterally administrable formulations that are useful include those containing the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer system. Compositions for sustained release or implantation may include pharmaceutically acceptable polymeric or hydrophobic materials such as emulsions, ion exchange resins, sparingly soluble polymers or sparingly soluble salts.

  The pharmaceutical compositions of the present invention may be manufactured, packaged or sold in a formulation suitable for buccal administration. Such formulations may be present, for example, in the form of tablets or lozenges made using conventional methods and include, for example, 0.1-20% (w / w) active ingredient, Orally dissolvable or degradable compositions and optionally a balance comprising one or more additional ingredients as described herein may be included. Alternatively, formulations suitable for buccal administration may include a powder comprising the active ingredient or an aerosol or spray solution or suspension. Such powdered, aerosolized or sprayed formulations, when dispersed, preferably have an average particle or droplet size in the range of about 0.1 to about 200 nanometers and are further described herein. It may contain one or more additional ingredients as described in the document.

  As used herein, “additional components” include, but are not limited to: additives; surfactants; dispersants; inert diluents; granulating and disintegrating agents; Lubricants; sweeteners; flavoring agents; coloring agents; preservatives; physiologically degraded compositions such as gelatin; aqueous media and solvents; oily media and solvents; suspending agents; Emulsifiers, demulsifiers; buffers; salts; thickeners; excipients; emulsifiers; antioxidants; antibiotics; antibacterial antifungal agents; stabilizers; and pharmaceutically acceptable polymeric or hydrophobic materials Contains one or more. Other “further ingredients” that may be included in the pharmaceutical compositions of the invention are known in the art and are described, for example, in Genaro, ed. (1985, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA), which is incorporated herein by reference.

  Typically, the dose of a compound of the invention that may be administered to an animal, preferably a human, is not limited to the type of animal, the type of disease state being treated, the age of the animal and the administration It can vary depending on several factors, including the pathway.

  The compound may be administered to the animal several times a day, or it may be once a day, once a week, once every two weeks, less frequently, such as once a month, or every few months. It may be administered once or less frequently, such as once a year or less. The number of doses will be readily apparent to skilled technicians and is not limited to several types such as, but not limited to, the type and severity of the disease being treated, the type and age of the animal, etc. It will depend on the factors.

  The invention will now be described with reference to the following examples. These examples are provided solely for the purpose of illustration, and the invention is not limited by these examples, but rather becomes apparent as a result of the teachings provided herein. All modifications are included.

Example 1: Methods for assaying combination compositions Established methods for assessing the effects of drugs acting on respiratory control are closed systems in which important factors affecting respiration can be tightly controlled and tracked Is to create. For example, control systems are established for oxygen concentration, carbon dioxide concentration and atmospheric pressure.

  For animal-based assessment, systems are available that allow assessment of multiple respiratory function measurements across the body or only the nose. Also, animal models of respiration (eg, guinea pigs, dogs, rodents) combined with the use of allergies, inflammation, COPD and anesthetic analgesics have been established. As a non-limiting example, the Loveless Respiratory Research Institute (Albuqueque, NM) has extensive experience in establishing such models as part of an evaluation for new drugs and environmental exposure applications.

  Similar systems have been established for human studies. Hildebrandt et al. (Blood 2002; 99: 1552-1555) described the protocol used for the evaluation of N-acetylcysteine under varying oxygen and carbon dioxide concentration conditions. In addition, the United States military (the Naval Aerospace Medical Research Command, Pensacola FL., US Army Research Institute of Environmental Medicine, Natick, MA) et al. Aviat Space Environ Med 2003; 74: 1190-7).

  Finally, inpatients connected to mechanical ventilators provide an opportunity to closely assess the effects of drugs on breathing. Oxygen and carbon dioxide levels can be controlled in an environment where respiratory parameters are measured in minute-by-minute basis.

  In addition to the animal and human based systems, there is an emerging field where certain biochemical markers are used to indicate chronic oxidative stress derived from hypoxia. One example is the use of various isoprostanes to indicate oxidative stress (Crakoski JL and Durand T. Fundam Clin Pharmacol 2006; 20: 417-27).

  The disclosures of each and every patent, patent application and publication cited herein are hereby incorporated by reference in their entirety.

  Although the invention has been disclosed with reference to specific embodiments, it is obvious that other embodiments and modifications of the invention may be derived by those skilled in the art without departing from the true spirit and scope of the invention. is there. The appended claims are intended to cover all such embodiments and equivalent variations.

Illustrates the complex and interrelated properties of mammalian respiratory control. Factors affecting normal respiratory control are specifically explained. Normally, respiratory drivers can act across a range of conditions, and carbon dioxide and oxygen levels are the main drivers and work in an interrelated manner. It specifically explains the factors that affect impaired respiratory control. A wide range of factors work individually or in combination to reduce respiratory motives resulting in respiratory arrest or inadequate breathing. The ultimate ending is hypoxia with cardiovascular, neurological and / or metabolic consequences. Describes the factors considered for effective medication of impaired respiratory control. Drugs are useful to help restore respiratory motives through defined routes or by improving air flow in the upper respiratory tract. The ultimate ending is to reduce impaired breathing (eg apnea, hypopnea, hypoventilation), hypoxia and related consequences in one embodiment of the invention.

Claims (25)

The therapeutic composition is
a. A first composition comprising an S-nitrosothiol first compound; and b. A second composition comprising a second compound that is not an S-nitrosothiol compound, and the second compound has an activity to stabilize respiratory rhythm:
A therapeutic composition for stabilizing respiratory rhythm.   A method of stabilizing the respiratory rhythm of a mammal comprising administering the therapeutic composition of claim 1 to the mammal.   The therapeutic composition according to claim 1, wherein the second compound is a compound having an ability to stabilize a respiratory rhythm.   4. The method of claim 3, wherein the second compound is selected from the group consisting of carbonic anhydrase inhibitors, respiratory stimulants, narcotic antagonists and hormones.   The therapeutic composition of claim 1, wherein the second compound is a compound having activity to increase patency of the upper airway.   6. The method of claim 5, wherein the second compound is selected from the group consisting of serotonin agonists, serotonin antagonists, tetracyclic antidepressants, agents that act on dopamine, and agents that act on norepinephrine.   The therapeutic composition according to claim 1, wherein the second compound is a compound having an activity of promoting arousal.   The therapeutic composition according to claim 1, wherein the second compound is a compound having an activity of reducing epileptic seizures.   The therapeutic composition according to claim 1, wherein the second compound is a compound having an activity of increasing patency of the upper airway by reducing inflammation.   10. The method of claim 9, wherein the second compound is selected from the group consisting of an antihistamine, a leukotriene antagonist, a 5-lipoxygenase inhibitor, a steroid and a COX-2 inhibitor.   The therapeutic composition according to claim 1, wherein the second compound is a compound having an activity of reducing respiratory motive.   12. The method of claim 11, wherein the second compound is selected from the group consisting of an opioid analgesic, a sedative hypnotic, and a general anesthetic.   The therapeutic composition according to claim 1, wherein the second compound is a compound having an activity of improving lung function.   14. The method of claim 13, wherein the second compound is selected from the group consisting of steroids, bronchodilators and anticholinergics.   The composition of claim 1, further comprising a third compound that is an S-nitrosothiol compound.   The composition of claim 1, further comprising a third compound that is not an S-nitrosothiol compound.   A method for stabilizing the respiratory rhythm of a mammal comprising administering to the mammal a therapeutic composition according to one of claims 8 or 9.   A method of stabilizing the respiratory rhythm of a mammal, comprising administering the therapeutic composition of claim 1 to the mammal, further comprising treating the mammal with a ventilatory assist device.   The method of claim 18, wherein the ventilation assist device is selected from the group consisting of a mechanical ventilator, a CPAP device, and a BiPAP device.   A pharmaceutical composition comprising the therapeutic composition of claim 1 and a pharmaceutically acceptable carrier.   14. A method for stabilizing the respiratory rhythm of a mammal comprising administering the therapeutic composition of claim 13 to the mammal.   24. The method of claim 21, wherein the route of administration is selected from the group consisting of parenteral, oral and buccal routes.   23. The method of claim 22, wherein the parenteral route of administration is selected from the group consisting of transdermal, intravenous, intramuscular and intradermal routes of administration.   24. The method of claim 22, wherein the composition is administered by at least two routes of administration. a. A first composition comprising an S-nitrosothiol first compound; and b. A second composition comprising a second compound that is not an S-nitrosothiol compound, wherein the second compound is a fine ventilator (V at the level of the brainstem respiratory control center in the nucleus tractus solitarius) _A composition having an activity to increase _E );
The comprises the step of administering a comprising at therapeutic composition to an individual, a method for increasing the fine ventilation (V _E) at the level of the brainstem respiratory control center in the individual's arc Tabakaku.

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